Abstract
Valid molecular markers need to be implemented in clinical trials to fulfill the demand of a risk-adapted and more individualized multimodal therapy of locally advanced primary rectal cancer. In this study, the expression of the inhibitor-of-apoptosis (IAP) protein survivin was evaluated in pretreatment biopsies and corresponding posttreatment resection specimens, and was correlated to histo-pathological tumor characteristics and clinical follow-up. One hundred sixteen patients with stage II/III rectal cancer treated with 5-FU-based neoadjuvant radiochemotherapy (RCT) at a single university medical centre within the German Rectal Cancer Trials were investigated. Survivin expression in pretreatment biopsies and surgical resection specimens were determined by immunohistochemistry by two independent institutions and correlated with histopathologic parameters, tumor recurrences, disease-free (DFS), and overall cancer-specific survival (CSS). In pretreatment biopsies, a higher survivin expression correlated with advanced ypT (P = 0.026) and ypUICC (P = 0.05) stage as well as DFS (P = 0.038) after preoperative RCT. High posttreatment survivin levels were associated with advanced ypT stage (P = 0.03) and residual lymph node metastases (P = 0.04). Moreover, neoadjuvant RCT resulted in a significant downregulation of survivin expression (P < 0.0001). A failure of RCT-induced downregulation was associated with development of distant metastases (P = 0.0056) and cancer-related death (P = 0.026), and correlated significantly with DFS (P = 0.011*/0.02**) and CSS (P = 0.0017*/0.01**) in uni-* and multivariate** analyses. Survivin expression displays a marker with prognostic utility in rectal cancers. These results underline the potential of survivin to monitor individual response to RCT and encourage anti-survivin strategies in multimodal rectal cancer therapy within future randomized clinical trials.
Highlights
Neoadjuvant radiochemotherapy (RCT) followed by total mesorectal excision (TME) has become standard treatment in locally advanced UICC (Union International contre le Cancer) II/III rectal cancer within the last decade [1]
Reliable molecular markers may help to individually tailor multimodal treatment regimens by risk-adapted or novel therapeutic approaches
We investigated the predictive and prognostic relevance of survivin expression both in pre-treatment biopsies and corresponding surgical specimens of 116 patients with locally advanced rectal cancer treated with standardized 5-FU based neoadjuvant RCT
Summary
Neoadjuvant radiochemotherapy (RCT) followed by total mesorectal excision (TME) has become standard treatment in locally advanced UICC (Union International contre le Cancer) II/III rectal cancer within the last decade [1]. The smallest member of the inhibitor-of-apoptosis (IAP) family is a multifunctional protein that is reported to interact at the crossroads of disparate molecular networks of cellular division, intracellular signaling and apoptosis [6, 7] In this context, one of the signature features of survivin is its ability to associate with multiple protein partners, and to localize to disparate subcellular compartments [8, 9]. Several preclinical in vitro studies have demonstrated that targeting survivin’s expression by the use of small interfering RNAs, antisenseoligonucleotides and small molecule repressors radiosensitize tumor cells and reduces tumor growth in vivo. Due to these properties, survivin has been proposed as a molecular target for anticancer therapies [12, 13]
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